The present invention relates to a method and composition for antitumor therapy, and more particularly to combination therapy using a chemotherapeutic drug and an immunostimulating cytokine. Sequential administration of these two components, both encapsulated in liposomes, is shown to have a significant antitumor effect as compared to administration of the individual components, in free form or in liposomes.
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Despite prolific research in the area of cancer chemotherapy, such treatment remains far from satisfactory. The inability of chemotherapeutic drugs to reach the tumor site, intrinsic and acquired cross-resistance to multiple chemotherapeutic agents, and, especially, the high toxicity of many of these agents all contribute to treatment failures.
The use of immunostimulating cytokines, such as IL-2 and interferon-xcex1, has proven to be effective in treatment of a proportion of patients with malignancies such as melanoma and renal cell carcinoma, both alone and in combination with other therapeutic agents. However, major problems limit their wide clinical use, including rapid plasma clearance, biodistribution to nonrelevant tissues, and high toxicity. Furthermore, their efficacy has been low in treatment of the most common tumors, e.g. colorectal, mammary, prostate, and lung carcinomas.
The present invention includes, in one aspect, a method of antitumor therapy, which comprises administering to a subject in need of such treatment, a therapeutically effective amount of a combination of a chemotherapeutic drug and an immunostimulating cytokine, both encapsulated in liposomes. In another aspect, the invention provides a composition for use in antitumor therapy, which comprises such a combination of a chemotherapeutic drug and an immunostimulating cytokine, both encapsulated in liposomes. Administration of the combination produces a greater therapeutic effect than a combination of the effects produced by the liposome-encapsulated components administered individually.
The invention also includes a method of antitumor therapy in which a chemotherapeutic drug, encapsulated in liposomes, is administered in combination with a cytokine, which may or may not be encapsulated in liposomes. In this method, the drug is encapsulated in liposomes which contain about 1-10 mole percent of a lipid having a polar head group derivatized with a polyethylene glycol (PEG) chain which has a molecular weight of between 750 and 10,000 daltons. The therapeutic effect of this combination is greater than a combination of the effects produced by the liposome-encapsulated drug and the cytokine administered individually.
In all cases, administration of the cytokine preferably follows administration of the liposome-encapsulated drug.
The chemotherapeutic drug is preferably selected from cis-platin, a chemotherapeutic anthraquinone, and a topoisomerase I inhibitor, such as camptothecin or a camptothecin analog. More preferably, the drug is adriamycin (doxorubicin), in which case the liposome-encapsulated form of the drug is preferably DOXIL(copyright), a polyethylene glycol-coated liposomal doxorubicin.
The immunostimulating cytokine is preferably selected from the group consisting of interleukin-2 (IL-2), IL-12, IL-15, IL-18, IFN-xcex3, IFN-xcex1, IFN-xcex2, TNF-xcex1, G-CSF, and GM-CSF. More preferably, the cytokine is IL-2.
The encapsulating liposomes employed in the composition and method preferably contain at least one lipid selected from dimyristoyl phosphatidyl choline (DMPC), dimyristoyl phosphatidyl glycerol (DMPG), 1,2-distearoyl-3-trimethylammonium propane (DSTAP), phosphatidyl choline, phosphatidyl ethanolamine, and cholesterol.
The liposomes may be small unilamellar vesicles (SUV), defined as having a mean diameter of approximately 20 to 100 nm, or large unilamellar vesicles (LUV), defined as having a mean diameter of approximately 100 to 200 nm. Such liposomes preferably contain about 1-10 mole percent of a lipid having a polar head group derivatized with a polyethylene glycol (PEG) chain which has a molecular weight of between 750 and 10,000 daltons.
Alternatively, the liposomes may be large multilamellar vesicles (MLV) having a mean diameter of approximately 250 to 2000 nm. The MLV may also contain a PEG-derivatized lipid as described above.
In preferred embodiments, the chemotherapeutic drug is encapsulated in vesicles having a mean diameter of approximately 50 to 120 nm, and containing about 1-10 mole percent of a lipid having a polar head group derivatized with a polyethylene glycol (PEG) chain as described above. In another preferred embodiment, the cytokine is encapsulated in liposomes containing dimyristoyl phosphatidyl choline (DMPC) plus 0 to 50 mole percent of at least one lipid selected from dimyristoyl phosphatidyl glycerol (DMPG) and 1,2-distearoyl-3-trimethylammonium propane (DSTAP).
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.